Production of stabilized divinyl ether suitable for general anesthesia



Patented June 23, 1936 PRODUCTION OF STABILIZED DIVINYL ETHER SUITABLE FOR GENERAL AN- ESTHESIA Randolph T. Major, Plainfleld, and William L. Rnigh, Princeton, N. J., assignors to Merck & 00., Inc., Rahway, N. 1., a corporation of-- New Jersey No Drawing. Original application June 21, 1933,

Serial No. 676,926.

Divided and this application September 7, 1933, Serial No. 688,462

10 Claims. (01. 23-250) This application is a division of our copending application Serial No. 676,926, filed June 21, 1933.

The present invention relates more particularly to the production of a stabilized divinyl ether 5 suitable for use as a general inhalation anesthetic.

In'our copending application, Serial No. 551,098, we have described the physical and chemical properties of true divinyl ether and processes for producing it in highly pure form which renders it useful for many technical purposes and for anesthetic preparations.

The process for producing this pure divinyl ether, as described in the said copending application, comprises the steps of reacting upon 5,13

dihalogen-diethyl ether with alkali hydroxide in an autoclave under constant stirring to prevent the formation of any crust of alkali upon the surface of the reaction mixture; using appropriate distillation and condensation means, and pass- 0 ing a stream of ammonia gas throughout the reaction, distillingand condensing systems during the conduct of the entire process. The process thus set forth produces as a final product a divinyl ether substantially free from aldehyde,

5 ethylene'oxide, 1,4-dioxane, p-chloroethyl-vinyl ether, etc. In this manner, we were able to produceand isolate for the first time a true divinyl ether showing decidedly different physical con These findings, together with analyses and molecular weight determinations, clearly distinthe old literature, and indicated that'it is substantially pure CaHa.O.C2Ha.-

Based upon the pharmacological studies of Leake and Chen (Proc. Soc. Exper. Biol. and i5 Med, 1930,"XXXVIII) of the anesthetic properguisheli our new product from those described in ties of unsaturated ethers in. general, this product, therefore, was indicated on theoretical grounds to be a promising new anesthetic, especially because it was in highly pure formand contained no injurious by-products, such as aldehyde, ethylene oxide, 1,4-dioxane, and p-chloroethylvinyl ether, which are components of the mixtures prepared by the older methods and which had previously been assumed to be pure divinyl ether. Recent clinical results have justified the theoretical conceptions as to relatively low toxicity and anesthetically important physical and chemical properties.

v So, also, the new product readily lends itself to numerous technical usesfor instance as a solvent for fats, oils and waxes, and for their extraction, and as an intermediate in the preparation of various solid and semi-solid glassrlilre polymers. On account of its definite composition and properties, it is susceptible to more posi tive and reliable adaptation, to its several possible uses, as compared with the hitherto known preparation of indefinite and varying composition. These advantages are ascribable to'the fact that true divinyl ether contains no higher boiling material and no active foreign material,

such as acetaldehyde, which reacts with. many exposure, especially when in a warm place and/or exposed to light.

Such decomposition, deterioration and polymerization obviously render the etherunfit, not

only for anesthetic uses, but for general technical uses as a solvent and otherwise as well.

It has now been found by us that this new pure unsaturated ether can be effectively protected "asfitfo'rth in our copending application Serial No. 676,926, of which this application is a division. Groups of substances which satisfactorily inhibit decomposition are various polyphenols, ammonia, and phenolic and non-phenolic aromat- V ic amines. We have found as especially satisfactory, according to the ultimate requirements, such compounds as hydroquinone and py ogallol, ammonia, antipyrine, quinine, phenyl-a-naphthylamine, phenylp-naphthylamine, o-nitroaniline, p-phenylen-diamine, ,p-toluidine, diphenylenediamine', p-nitrophenylhydrazine, p-

- non-toxic in the quantities employed, and nonvolatile. For technical uses of the ether, the chosen inhibitor must be chemically inert for the specific purposes of the use. Such limitations and appropriate selections will be readily understood according to the nature of the materials coming into consideration:

To further protect the ether from decomposition or deterioration, it is also desirable that the vinyl ether be packaged in containers freed from air or with an atmosphere of an inert gas such as nitrogen.

The practical application of the process for the production of a stabilized divinyl ether comprises the solution of the given appropriate inhibitor in approximately from one part to parts, to as low as one part per 100,000 parts of the ether, depending upon the inhibitor employed and the requirement for the particular ultimate use. Obviously the inhibiting action of these several agents is in general more certain and positive with the relative increase in quantity within reasonable limits, and the specific material selected, as well as the quantities used, may be convenie'ntly modified to adapt the process to the special requirements as indicated.

Thus, in the special case of preparing the divinyl ether for use as a general'anesthetic, the inhibiting agent is preferably such a substance as phenyl-e-naphthylamine, because of its relatively low toxicity. This low toxicity again in turn makes it possible to employ relatively larger proportional quantities to insure more positive stabilization. Very satisfactory results have been obtained for this purpose by adding one part of phenyl-a-naphthylamine to about 10,000 parts of the ether, although this latter inhibitor exercises a demonstrable inhibitory eflect in concentrations as low as l:l00,000.

As a general guide for the quantitative determinations as directed to various practical applications, it has been found that the following inhibitors were generally effective in concentrations of about 1210,000: hydroquinone, pyrogallol, phenyl a naphthylamine, amine, o-nitroaniline, antipyrine, p-phenylenediamine, p-toluidine, diphenylenediamine, p-nitrophenylhydrazine, quinine, p-aminophenol, N- methylaminophenol, and N- isopropylaminophenol.

The following inhibitors have been used in concentrations as low as 1150,000 with appreciable effect: p-phenylenediamine, hydroquinone, phenyl-a-naphthylamine, and p-aminophenol.

The further steps of the process comprising the packaging of the material in vacuo or with an atmosphere of nitrogen, for instance, if required,

may be practiced by any of the known or condivinyl etli'er, stabilized in the manner indicatgg when intended for use as a general inhalation anesthetic, to add a quantity of an anti-freeze agent, which, for such uses, should be non-toxic, soluble in the divinyl ether and in water,' and volatile in the mixture with the ether. Such an agent is available, for example, in ethyl alcohol, where it has been found that a quantity of about 3.5% by volume is generally suflicient. The quantity of ethyl alcohol for serving as an antifreeze agent with the vinyl ether has been found to range from about 1.5% to about 5%. Excessive quantities of alcohol are to be avoided to prevent the collection of unevaporated alcohol on the ume of ethyl alcohol.

We claim as new:

1. An inhalation anesthetic, comprising divinyl ether, a stabilizing agent consisting of a rela tively non-toxic aryl amine, and an alcoholic anti-freeze ingredient.

2. An inhalation anesthetic, comprising divinyl ether, phenyl-e-naphthylamine and ethyl alcohol.

3. A stabilized divinyl ether solution containing substantially one part of an aromatic amine to from 100 to 100,000 parts of the ether, and from about 1.5% to 5% of ethyl alcohol.

4. The process of producing a preparation of divinyl ether suitable for use as an inhalation anesthetic, comprising the steps of dissolving therein an aromatic amine and ethyl alcohol.

5. The method of preserving and packaging divinyl ether which consists of dissolving therein one part of an aromatic amine to from 10,000 to 100,000 parts of -the ether and from about 1 to 5% of ethyl alcohol, and packaging the same in a container substantially freed from air.

6. The method of preserving and packaging divinyl ether which consists of dissolving therein one part of an aromatic amine to from 10,000 to 100,000 parts of the ether and from about 1 /z% to 5% of ethyl alcohol, and packaging the same in an atmosphere of an inert gas.

7. The method of preserving and packaging divinyl ether for anesthetic use which consists of dissolving therein phenyl-a-naphthylamine and ethyl alcohol, and placing the same in a container substantially free from air.

8. The method of preserving and packaging divinyl ether for anesthetic use which consists of dissolving therein phenyl-e-naphthylamine and ethyl alcohol, and packaging the same in an atmosphere of an inert gas.

9. The process of producing a preparation of divinyl ether suitable for use as an inhalation anesthetic which consists of dissolving therein phenyl-a-naphthylamine and ethyl alcohol, and packaging the same in an atmosphere of nitrogen.

10. An inhalation anesthetic comprising divinyl ether, a stabilizing agent consisting of a relatively non-toxic aryl amine, and an'anti-freeze ingredient.

RANDOLPH T. MAJOR.

' WILLIAM L. RUIGH. 

